Methyl Dichloroacetate

(1; R = Me)

[116-54-1]  · C3H4Cl2O2  · Methyl Dichloroacetate  · (MW 142.97) (2; R = Et)

[535-15-9]  · C4H6Cl2O2  · Ethyl Dichloroacetate  · (MW 157.00) (3; R = i-Pr)

[25006-60-4]  · C5H8Cl2O2  · Isopropyl Dichloroacetate  · (MW 171.03)

(synthesis of a-chloroglycidic esters1 and/or 3-chloro 2-keto ester isomers1,2 (Darzens reaction); 2,2-dichloro esters (alkylation);3 1,2-dialkoxycarbonylchlorocyclopropanes (Michael reaction);4 precursor5 for Reformatsky reagents; precursor for 1,1-dithioalkyl (or aryl) acetates6)

Physical Data: (1) bp 143 °C; d 1.3774 g cm-3. (2) bp 157 °C; d 1.2827 g cm-3. (3) bp 164-165 °C; d 1.2053 g cm-3.

Solubility: sol ether, acetone, alcohol, THF, chloroform.

Handling, Storage, and Precautions: lacrymatory; handle in a well-ventilated fume hood. The reagents are quite stable at rt under neutral conditions.

Introduction.

Dichloracetic esters have a very acidic a-proton which allows, after deprotonation with the appropriate bases, Darzens reaction with carbonyl compounds and imines, alkylation, and Michael reactions followed by cyclization with acrylic esters.

Synthesis of a-Chloroglycidic Esters, b-Chloro a-Keto Esters, and 2,2-Dichloro Esters.

One of the most important applications of dichloro acetates has been found in the synthesis of a-chloroglycidic esters1 and their b-chloro a-keto ester isomers via the Darzens reaction in the presence of potassium or sodium alcoholates in alcohols.7 When applied to aromatic aldehydes in aprotic media this reaction gives a-chloropyruvates.2 The reaction also applies to various carbonyl compounds, such as carbohydrates8 and steroids.9 The same reaction was developed from the corresponding 2-dichloromethyl-4,4-dimethyl-2-oxazolidine (eq 1).10

In the presence of imines this reaction gave analogous 1-chloro-1-alkoxycarbonylaziridines (eq 2).11

Tandem Darzens-hydrolysis reactions have been used for the synthesis of natural 3-hydroxy 2-keto esters,12 while tandem Darzens-isomerization-dehalogenation gave rise to a-keto esters (eq 3).8

Lithium dichloroenolates have been prepared by deprotonation of dichloracetates with Lithium Diethylamide,3 Lithium Diisopropylamide,13 Lithium Dicyclohexylamide,14 or n-Butyllithium.15 Coupling of these anions with carbonyl compounds afforded 3-hydroxy-2,2-dichloroesters3,15 or a-chloroglycidic esters15 at rt, while 2,2-dichloroalkanoates have been prepared by alkylation of bromoalkanes in the presence of HMPA (eq 4).3,13,16

However, vicarious substitution of nitroarenes by dichloroacetate potassium enolates (Potassium t-Butoxide in DMF) only gave the corresponding a-chlorobenzyl esters via addition of enolates and subsequent hydrochloric acid elimination (eq 5).17

Preparation of 1,2-Dialkoxycarbonyl-1-chlorocyclopropanes.

Dichloroenolates from dichloroacetates have been involved in a tandem Michael-cyclization reaction with acrylic esters in the presence of lithium hydride,18 electrogenerated bases,19 or under mildly basic phase-transfer conditions20 (eq 6).

Chlorine abstraction by metals (Zn/Ag)21 or under electrocatalysis22 with a zinc sacrificial anode in the presence of a nickel complex led to the formation of the intermediate Reformatsky reagents MCHCl-CO2R and allowed preparations of 3-hydroxy-2-chloroalkanoates or glycidic esters on coupling with carbonyl compounds (eq 7).

The corresponding copper carbenoids, obtained intermediately by reaction of copper in DMSO, gave mixtures of fumarates and maleates.23

Selective Synthesis of 2,4-Dichloroalkanoates and 2,2-Dichloroalkanoates.

Addition of dichloroacetates to 1-alkenes by a radical pathway can lead to the formation of both 2,4-dichloroalkanoates and 2,2-dichloroalkanoates, depending on reaction conditions.24 When performed in the presence of 0.7 mol % dichlorotris(triphenylphosphine)ruthenium(II)25 or copper(I) chloride-1,10 phenanthroline complexes,26 2,4-dichloroalkanoates are formed exclusively, while 2,2-dichloroalkanoates are formed preferentially in the presence of peroxides (eq 8).27 The mechanism of this reaction has been fully investigated.25,28 Butadiene can also be used as a substrate.29

Miscellaneous.

Dialkyl-6 and diarylthioacetates6,30 can be easily prepared by substitution of dichloroacetates by thiolates. Reaction with Phosphorus(III) Chloride occurs in the presence of Triethylamine and leads to the formation of the corresponding dichlorophosphines.31

Related Reagents.

Dichloroacetonitrile; Methyl Chloroacetate.


1. Castro, B.; Villieras, J.; Ferracutti, N. CR(C) 1969, 268, 1403.
2. (a) Martynov, V. F.; Titov, M. I. ZOB 1962, 32, 319 (CA 1962, 57, 12 373c). (b) Mc Donald, R. M.; Schwab, P. A. JOC 1964, 29, 2459.
3. Villiéras, J.; Disnar, J. R.; Perriot, P.; Normant, J. F. S 1975, 524.
4. Kawakami, Y.; Tajima, K.; Tsuruta, T. T 1973, 29, 1179.
5. Sibille, S.; d'Incan, E.; Leport, L.; Perichon, J. TL 1986, 27, 3129.
6. (a) Lerner, L. M. JOC 1976, 41, 2228. (b) Massiot, G.; Mulamba, T.; Levy, J. BSF 1982, 241.
7. (a) Takeda, A.; Wada, S.; Fujii, M.; Tanaka, H. BCJ 1970, 43, 2997. (b) Tsuboi, S.; Furutani, H.; Takeda, A. S 1987, 292.
8. (a) Coutrot, P.; Grison, C.; Tabyaoui, M.; Czernecki, S.; Valery, J. M. CC 1988, 1515. (b) Coutrot, P.; Grison, C.; Tabyaoui, M. TL 1993, 32, 5089.
9. (a) Amos, J.; Castro, B. BSF 1974, 2559. (b) Amos, J.; Castro, B. BSF 1991, 550.
10. Combret, J. C.; Meghni, A.; Postaire, D.; Tekin, J. TL 1991, 32, 87.
11. (a) Coutrot, P.; El Gadi, A. JOM 1985, 280, C11. (b) Protas, J.; Coutrot, P.; El Gadi, A. Acta Crystallogr. 1989, C45, 1189.
12. (a) Moraud, B.; Combret, J. C. CR(C) 1973, 277, 523. (b) Bicherova, I. T.; Turik, S. V.; Kornilov, V. I.; Zhdanov, Y. A. ZOB 1989, 59, 1676 (CA 1990, 112, 158 787c).
13. Hayes, T. K.; Villani, R.; Weinreb, S. M. JACS 1988, 110, 5533.
14. Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010.
15. Mamedov, V. A.; Valeeva, V. N.; Antokhina, L. A.; Nuretdinov, I. A. IZV 1992, 8, 1870 (CA 1993, 118, 124 325j).
16. Larchevèque, M.; Perriot, P.; Petit, Y. S 1983, 297.
17. Makosza, M.; Sienkiewicz, K.; Wojciechowski, K. S 1990, 850.
18. Kawakami, Y.; Tajima, K.; Tsuruta, T. T 1973, 29, 1179.
19. (a) Shono, T.; Kise, N.; Suzumoto, T. JACS 1984, 106, 259. (b) Shono, T.; Ishifune, M.; Ishige, O.; Uyama, H.; Kashimura, S. TL 1990, 31, 7181.
20. Yan, C.; Kong, Q.; Lu, W.; Wu, J. SC 1992, 22, 1651.
21. Furstner, A. JOM 1987, 336, C33.
22. Conan, A.; Sibille, S.; Perichon, J. JOC 1991, 56, 2018.
23. Tezuka, Y.; Hashimoto, A.; Ushizaka, K.; Imai, K. JOC 1990, 55, 329.
24. Guerrini, P.; Sorba, J.; Lefort, D. CR(C) 1971, 272, 1690.
25. Matsumoto, H.; Nikaido, T.; Nagai; Y. JOC 1976, 41, 396.
26. Julia, M.; Saussine, L.; Le Thuillier, G. JOM 1979, 174, 359.
27. Kharasch, M. S.; Urry, W. H.; Jensen, E. V. JACS 1945, 67, 1626.
28. Sorba, J.; Fossey, J.; Lefort, D. BSF 1977, 967.
29. Vit, Z.; Hajek, M. CCC 1987, 52, 1280.
30. Mori, T.; Inokuchi, H. CL 1992, 1873.
31. Malenko, D. M.; Gololobov, Y. G. ZOB 1979, 49, 2384 (CA 1980, 92, 94 504s).

Jean Villiéras & Monique Villiéras

Nantes University, France

Philippe Coutrot & Claude Grison

Nancy University, France



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.